ORGANIC LETTERS
An Efficient Method for Construction of the Angularly Fused 6,3,5-Tricyclic Skeleton of Mycorrhizin A and Its Analogues
2009 Vol. 11, No. 3 629-632
Binxun Yu,† Tuo Jiang,† Weiguo Quan,† Junpeng Li,† Xinfu Pan,† and Xuegong She*,†,‡ Department of Chemistry, State Key Laboratory of Applied Organic Chemistry, Lanzhou UniVersity, Lanzhou, 730000, P. R. China, and State Key Laboratory for Oxo Synthesis and SelectiVe Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, P. R. China
[email protected] Received November 21, 2008
ABSTRACT
The angularly fused 6,3,5-tricyclic system is readily generated via a cascade cyclization under acid promotion. The reaction proceeds at room temperature with high stereochemical fidelity from the electrophilic center of the epoxide to the cyclopropane product. This methodology provides a potentially useful approach for the synthesis of mycorrhizin A and its analogues.
The antibiotic mycorrhizin A (1a, Figure 1), was first isolated and characterized by Wickberg and Trofast1a from a sterile mycelium of an endomycorrhizinal fungus in 1977. Several analogues of 1, compounds 2-4, have been obtained from other culture filtrates of the fungus.1b-e Biologically, these compounds possess varying degrees of antifungal and antibiotic activity.1f However, efforts directed toward the synthesis of the basic angularly fused 6,3,5-tricyclic skeleton have been limited to date.2,3 Only two elegant strategies have been reported for such ring systems: an interesting synthetic approach was disclosed by Smith’s group,2 in which an intramolecular SN2′ reaction was utilized for construction of the cyclopropane ring, and Brown and co-workers reported †
Lanzhou University. Lanzhou Institute of Chemical Physics. (1) (a) Trofast, J.; Wickberg, B. Tetrahedron 1977, 33, 875. (b) Chexal, K. K.; Tamm, C.; Clardy, J.; Hirotsu, K. HelV. Chim. Acta 1979, 62, 1129. (c) Bollinger, P.; Zardin-Tartaglia, T. HelV. Chim. Acta 1976, 59, 1809. (d) Weber, H. P.; Petcher, T. J. HelV. Chim. Acta 1976, 59, 1821. (e) Shan, R.; Stadler, M.; Sterner, O. J. Antibiot. 1996, 49, 447. (f) Trofast, J., Ph.D. Thesis, Lund Institute of Technology, Lund, Sweden, 1978. ‡
10.1021/ol8026895 CCC: $40.75 Published on Web 01/13/2009
2009 American Chemical Society
that cycloaddition between diazomethane and an olefin, followed by extrusion of its nitrogen upon ultraviolet irradiation, led to the cyclopropane ring.3 In connection with our current studies dealing with the synthesis of cyclopropane derivatives,4 we describe herein a novel approach based on a cation-olefin cascade cyclization strategy for the construction of this tricyclic core system of mycorrhizin A and its analogues. Cation-induced cyclization provides a valuable means of constructing a variety of natural products.5 The reaction of an epoxy olefin with Lewis acids yields alcohols or ethers (2) (a) Koft, E. R.; Smith, A. B., III. J. Am. Chem. Soc. 1982, 104, 2659. (b) Smith, A. B., III; Huryn, D. M. J. Org. Chem. 1985, 50, 1342. (c) Smith, A. B., III; Yokoyama, Y.; Huryn, D. M.; Dunlap, N. K. Tetrahedron Lett. 1987, 28, 3659. (d) Smith, A. B., III; Yokoyama, Y.; Dunlap, N. K.; Hadener, A.; Tamm, C. Tetrahedron Lett. 1987, 28, 3663. (3) (a) Brown, R. F. C.; Teo, P. Y. T. Tetrahedron Lett. 1984, 25, 5585. (b) Brown, R. F. C.; Fallon, G. D.; Gatehouse, B. M.; Jones, C. M.; Rae, I. D. Aust. J. Chem. 1982, 35, 1665. (4) (a) Xie, X.; Yue, G.; Tang, S.; Huo, X.; Liang, Q.; She, X.; Pan, X. Org. Lett. 2005, 7, 4057. (b) Tang, S.; Xie, X.; Huo, X.; Liang, Q.; She, X.; Pan, X. Tetrahedron Lett. 2006, 47, 205.
potential of the corresponding epoxide-initiated 3-exo cyclizations warrants further investigation. We envisioned that the method involves the intramolecular cyclization of a π-nucleophile with an epoxide adduct. This reaction proceeds via an initial attack of the double bond on the epoxide ring leading to a cyclopropylcarbinyl cation intermediate 7, which could be trapped by the oxygen atom to provide the tricyclic product 6a (Scheme 1). However, the cyclopropylcarbinyl cation may be considered to belong to a nonclassical or a delocalized cation7 that is unstabilized without some substituents at appropriate positions; otherwise, ring-opening and rearrangment procedures would often occur.
Table 2. Synthesis of the Angularly Fused Tricyclic Skeleton via Acid-Mediated Intramolecular Cascade Cyclization Figure 1. Some representative fungal metabolites incorporating a 6,3,5-tricyclic skeleton.
of the cyclopentane, cyclohexane, and cycloheptane series via an intramolecular nucleophilic attack of the double bond on the incipient carbocation. However, in the field of cationinduced cyclization, transformation of an epoxide to a
Scheme 1. Design of an Epoxide-Initiated Cascade Cyclization
cyclopropane is still rare,6 and only a few examples of 3-exo cyclizations have been applied in the synthesis of natural products6d,e and with low yields. Hence, the synthetic
Table 1. Optimization of Reaction Conditions entry
acidic medium
equiv
1 2 3 4 5 6 7 8 9 10 11 12
SnCl4 BF3·OEt2 BF3·OEt2 BF3·OEt2 SnBr4 TiCl4 TMSOTf InCl3 ZnCl2 CF3COOH CF3SO3H p-TsOH
1.1 1.1 1.1 0.5 1.1 1.1 1.1 2 2 1.1 1.1 1.1
a
630
Yield of isolated product.
T (°C)
time (min)
yielda (%)
-20 to rt -20 to rt rt rt rt 0 to rt 0 to rt rt rt rt rt rt
60 60 3 3 15 10 10 60 60 60 5 120
44 70 98 45 34 20 25 trace 0 20 95 trace
a Condition A: BF3·OEt2 (1.1 equiv), CH2Cl2, rt. b Condition B: CF3SO3H (1.1 equiv), CH3CN, rt. c Condition C: BF3·OEt2 (2.2 equiv), CH2Cl2, rt. d Yield of isolated product. e Diastereoselectivity ratio was 3:1 determined by 1H NMR (400 MHz) analysis of crude reaction mixtures. f Accompanied by 5% unidentified byproduct.
To effect the proposed electrophilic olefin cyclization of allylic R,β-epoxy ketone 5a, an extensive investigation toward reaction condition was carried out (Table 1). Among all acids studied, BF3·OEt2 and CF3SO3H were found to be the ideal choices to promote 3-exo cyclization of the allylic epoxide to give the desired angularly fused 6,3,5-tricyclic product in satisfactory yields (Table 1, entries 3 and 11). Org. Lett., Vol. 11, No. 3, 2009
The reaction was complete in CH2Cl2 or CH3CN within 3-5 min at room temperature. Other Lewis acids (e.g., SnCl4, SnBr4, TiCl4, and TMSOTf) resulted in complex mixtures, while relatively weaker Lewis acids such as InCl3 and ZnCl2, as well as weaker protic acids (e.g., p-TsOH, CF3CO2H), resulted in no apparent reaction or only trace conversion (starting material was recovered).
Scheme 2. Chirality Transfer in the Epoxide-Initiated Cascade Cyclization
With this encouraging result in hand, we investigated more substrates under the optimized reaction conditions that were proven to be general and versatile, as shown in Table 2. For example, the R,β-unsaturated substrate 5b and lactone 5c were prepared and also successfully converted to the corresponding products 6b and 6c in 95% and 84% yields, respectively (entries 2 and 3). To our delight, olefinic epoxides 5d, 5e, and 5f similarly gave the corresponding products 6d, 6e, and 6f in excellent
Figure 2. ORTEP drawing of 6g (top CCDC no. 709206) and 6h (bottom CCDC no. 709207). Org. Lett., Vol. 11, No. 3, 2009
yields, demonstrating that substitutes on olefin are not essential to the cascade process (entries 4, 5, and 6). In most of the aforementioned examples, the reactions proceeded with uniformly exclusive diastereoselectivity. However, a pendant phenyl group was found to have a deleterious effect on this selectivity, providing 6f as a 3:1 diastereomeric mixture. We propose that the resulting benzylic ion, a more stable cyclopropylcarbinyl cation intermediate, was trapped relatively slowly by the oxygen resulting in the low stereoselectivity. The dihydroxyl adduct 5g underwent a 3-exo cascade cyclization to furnish the single diastereomeric adduct 6g, which demonstrated that the free hydroxyl group did not disturb the transformation (entry 7). Finally, it is interesting to note that in the case of entry 8, an unexpected triol cyclopropyl product 6h was obtained in moderate yield after quenching with aqueous sodium bicarbonate and no tricyclic product was observed. This indicated that the single-step transformation afforded the thermodynamically favored compound. With the optically active substrates 5i and 5j, acid-induced cyclization gave the expected products 6i and 6j in excellent yields with high stereochemical fidelity (Scheme 2).9 Moreover, these two cases disclosed that the presence of a carbonyl group adjacent to epoxide in the substrate did not play an important role in this reaction. The structures of all the products were established on the basis of spectroscopic data (see the Supporting Information). To assign the relative stereochemistry of the products beyond doubt, the structures of 6g and 6h were determined unambiguously by X-ray crystallographysthe former has a 5,6membered trans-fused configuration while the latter is an acyclic triol (Figure 2).10 It is noteworthy that compared with other products in Table 2, 6g prensents the most similar structural feature of mycorrhizin A, which enables the potential investigation for further diversity-oriented synthesis8 of the angularly fused 6,3,5-tricyclic natural products. In conclusion, we have developed an efficient method for constructing an angularly fused 6,3,5-tricyclic system via a cation-olefin cascade cyclization. The reaction can be (5) For reviews, see: (a) Thebtaranonth, C.; Thebtaranonth, Y. Cyclization Reactions; CRC Press: Boca Raton, 1994. (b) Taylor, S. K. Org. Prep. Proc. Int. 1992, 24, 245. (c) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131. (d) Johnson, W. S. Tetrahedron 1991, 47, xi-1. (e) Bartlett, P. A. Asymm. Synth. 1984, 3, 341. (f) Aziridines and Epoxides in Organic Synthesis; Yudin, A. K., Ed.; Wiley-VCH: Weinheim, 2006. (g) Domino Reactions in Organic Synthesis; Tietze, L. F., Brasche, G., Gericke, K. M., Ed.; Wiley-VCH: Weinheim, 2006. (6) (a) Conacher, H. B. S.; Gunstone, F. D. Chem. Comm. 1967, 984. (b) Canonica, L.; Ferrari, M.; Pagnoni, U. M.; Pelizzoni, F. Tetrahedron 1969, 25, 1. (c) Shirahama, H.; Hayano, K.; Kanemoto, Y.; Misumi, S.; Ohtsuka, T.; Hashiba, N.; Furusaki, A.; Murata, S.; Noyori, R.; Matsumoto, T. Tetrahedron Lett. 1980, 21, 4835. (d) White, J. D.; Jensen, M. S. J. Am. Chem. Soc. 1993, 115, 2970. (e) White, J. D.; Jensen, M. S. J. Am. Chem. Soc. 1995, 117, 6224. (7) Olah, G. A.; Prakash Reddy, V.; Surya Prakash, G. K. Chem. ReV. 1992, 92, 69. (8) Schreiber, S. L. Science 2000, 287, 1964. (9) Enantiomeric purity was determined by HPLC (see the Supporting Information). (10) Crystallographic data of 6g and 6h were deposited with the Cambridge Crystallographic Data Centre (CCDC nos. 709206 and 709207). The stereochemistries of the remaining products in Table 2 were assigned by analogy (see the Supporting Information for further details). 631
promoted by either Brønsted acid (CF3SO3H) or Lewis acid (BF3·OEt2), offering excellent yields and high stereochemical fidelity. Efforts directed toward the total synthesis of natural products bearing similar skeletons are currently being investigated in our laboratory. Acknowledgment. We are grateful for the generous financial support by the NSFC (QT program, 20572037,
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20732002), NCET-05-0879, and Gansu Science Foundation (3ZS051-A25-004). Supporting Information Available: Experimental details, H and 13C NMR spectra of products, and X-ray structure of 6g and 6h (CIF). This material is available free of charge via the Internet at http://pubs.acs.org. 1
OL8026895
Org. Lett., Vol. 11, No. 3, 2009
